TDP-43 pathology triggers neuroinflammation and cognitive impairment by inducing microglial necroptosis

Topic: Brain proteins, microglia and lab models

Pathological TAR DNA-binding protein-43 (TDP-43) is a defining feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). However, the mechanism by which TDP-43 pathology disrupts microglial function and drives neuroinflammation remains unclear. In this study, we demonstrated that cytoplasmically mis-localized TDP-43 exacerbated neuroinflammation, induced cell death, and impaired phagocytic function in microglial cells, primarily through receptor interacting serine/threonine kinase 3 (RIPK3)-dependent necroptosis. Pharmacological inhibition of RIPK3 with GSK872 markedly attenuated these pathological effects in vitro. These findings were further corroborated in a murine model with cytoplasmic TDP-43 mis-localization, where GSK872 treatment remarkably alleviated neuroinflammation and restored cognitive deficits. Mechanistically, our findings indicate that the nuclear depletion of TDP-43, resulted from its cytoplasmic mis-localization, impairs its ability to transcriptionally repress the Ripk3 gene, subsequently leading to RIPK3 upregulation and activation of RIPK3-dependent necroptosis. Collectively, our findings establish RIPK3-dependent necroptosis as a critical driver of TDP-43 pathology-mediated neuroinflammation and identified necroptosis as a promising therapeutic target in TDP-43-associated neurodegenerative disorders.

Key findings

• In this study, we demonstrated that cytoplasmically mis-localized TDP-43 exacerbated neuroinflammation, induced cell death, and impaired phagocytic function in microglial cells, primarily through receptor interacting serine/threonine kinase 3 (RIPK3)-dependent necroptosis.
• These findings were further corroborated in a murine model with cytoplasmic TDP-43 mis-localization, where GSK872 treatment remarkably alleviated neuroinflammation and restored cognitive deficits.
• Mechanistically, our findings indicate that the nuclear depletion of TDP-43, resulted from its cytoplasmic mis-localization, impairs its ability to transcriptionally repress the Ripk3 gene, subsequently leading to RIPK3 upregulation and activation of RIPK3-dependent necroptosis.
• Collectively, our findings establish RIPK3-dependent necroptosis as a critical driver of TDP-43 pathology-mediated neuroinflammation and identified necroptosis as a promising therapeutic target in TDP-43-associated neurodegenerative disorders.

Why it matters

This study found that cytoplasmic TDP-43 mis-localization induced microglial necroptosis through RIPK3, and that pharmacological inhibition of RIPK3 with GSK872 attenuated these effects in vitro and in a murine model. These findings identify necroptosis as a promising therapeutic target, but the work is in cells and mice, not humans.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/s44321-026-00394-9
• PubMed: 41807703
• Original source →
• Free full text: EMBO Molecular Medicine →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{guo2026-41807703,
  author  = {Guo, Shenrui and Jin, Hongfu and Sun, Hui and Huang, Shuo and Chen, Yuanyuan and Chang, Yuge and Zhang, Yu and Ding, Lin and others},
  title   = {{TDP-43 pathology triggers neuroinflammation and cognitive impairment by inducing microglial necroptosis}},
  journal = {EMBO Molecular Medicine},
  year    = {2026},
  doi     = {10.1038/s44321-026-00394-9},
  pmid    = {41807703},
  url     = {https://doi.org/10.1038/s44321-026-00394-9}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases Acta neuropathologica · 2007-07-25 · usefulness score 59/100 · How common it is
• Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets Signal transduction and targeted therapy · 2023-09-22 · usefulness score 58/100 · Lewy body dementia
• TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease Annals of neurology · 2007-05-01 · usefulness score 56/100 · Lewy body dementia
• TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration Nature neuroscience · 2021-12-16 · usefulness score 55/100 · TREM2 and immune genetics
• Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation The Journal of biological chemistry · 2008-02-27 · usefulness score 53/100 · Lewy body dementia
• Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases Nature reviews. Neuroscience · 2019-01-01 · usefulness score 52/100 · Inflammation and the immune system
• In vivo detection of microglial activation in frontotemporal dementia Annals of neurology · 2004-12-01 · usefulness score 48/100 · Inflammation and the immune system

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